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1.
Cell ; 2022 Mar 17.
Article in English | MEDLINE | ID: covidwho-1748151

ABSTRACT

Immune memory is tailored by cues that lymphocytes perceive during priming. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic created a situation in which nascent memory could be tracked through additional antigen exposures. Both SARS-CoV-2 infection and vaccination induce multifaceted, functional immune memory, but together, they engender improved protection from disease, termed hybrid immunity. We therefore investigated how vaccine-induced memory is shaped by previous infection. We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-γ and IL-10-expressing memory SARS-CoV-2 spike-specific CD4+ T cells than previously naive individuals. Although additional vaccination could increase humoral memory in previously naive individuals, it did not recapitulate the distinct CD4+ T cell cytokine profile observed in previously infected subjects. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.

3.
J Interferon Cytokine Res ; 41(10): 360-362, 2021 10.
Article in English | MEDLINE | ID: covidwho-1483361
5.
J Exp Med ; 218(8)2021 08 02.
Article in English | MEDLINE | ID: covidwho-1280019

ABSTRACT

Respiratory viral infections present a major threat to global health and prosperity. Over the past century, several have developed into crippling pandemics, including the SARS-CoV-2 virus. Although the generation of neutralizing serum antibodies in response to natural immunity and vaccination are considered to be hallmarks of viral immune protection, antibodies from long-lived plasma cells are subject to immune escape from heterologous clades of zoonotic, recombined, or mutated viruses. Local immunity in the lung can be generated through resident memory immune subsets that rapidly respond to secondary infection and protect from heterologous infection. Although many immune cells are required to achieve the phenomenon of resident memory, herein we highlight the pleiotropic functions of CD4 tissue resident memory T cells in the lung and discuss the implications of resident memory for vaccine design.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Immunologic Memory , Respiratory Tract Infections/immunology , Respiratory Tract Infections/virology , Animals , Humans , SARS-CoV-2/physiology , Species Specificity , Vaccination
6.
Cell ; 184(1): 169-183.e17, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1064911

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is causing a global pandemic, and cases continue to rise. Most infected individuals experience mildly symptomatic coronavirus disease 2019 (COVID-19), but it is unknown whether this can induce persistent immune memory that could contribute to immunity. We performed a longitudinal assessment of individuals recovered from mild COVID-19 to determine whether they develop and sustain multifaceted SARS-CoV-2-specific immunological memory. Recovered individuals developed SARS-CoV-2-specific immunoglobulin (IgG) antibodies, neutralizing plasma, and memory B and memory T cells that persisted for at least 3 months. Our data further reveal that SARS-CoV-2-specific IgG memory B cells increased over time. Additionally, SARS-CoV-2-specific memory lymphocytes exhibited characteristics associated with potent antiviral function: memory T cells secreted cytokines and expanded upon antigen re-encounter, whereas memory B cells expressed receptors capable of neutralizing virus when expressed as monoclonal antibodies. Therefore, mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks of antiviral immunity.


Subject(s)
COVID-19/immunology , COVID-19/physiopathology , Immunologic Memory , SARS-CoV-2/physiology , Adult , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , B-Lymphocytes/immunology , COVID-19/blood , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Male , Middle Aged , SARS-CoV-2/chemistry , Severity of Illness Index , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/immunology
7.
J Infect Dis ; 223(7): 1120-1131, 2021 04 08.
Article in English | MEDLINE | ID: covidwho-990725

ABSTRACT

BACKGROUND: To determine how serologic antibody testing outcome links with virus neutralization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we evaluated individuals for SARS-CoV-2 antibody level and viral neutralization. METHODS: We compared serum Ig levels across platforms of viral antigens and antibodies with 15 positive and 30 negative SARS-CoV-2 controls followed by viral neutralization assessment. We then applied these platforms to a clinically relevant cohort of 114 individuals with unknown histories of SARS-CoV-2 infection. RESULTS: In controls, the best-performing virus-specific antibody detection platforms were SARS-CoV-2 receptor binding domain (RBD) IgG (sensitivity 87%, specificity 100%, positive predictive value [PPV] 100%, negative predictive value [NPV] 94%), spike IgG3 (sensitivity 93%, specificity 97%, PPV 93%, NPV 97%), and nucleocapsid protein (NP) IgG (sensitivity 93%, specificity 97%, PPV 93%, NPV 97%). Neutralization of positive and negative control sera showed 100% agreement. Twenty individuals with unknown history had detectable SARS-CoV-2 antibodies with 16 demonstrating virus neutralization. Spike IgG3 provided the highest accuracy for predicting serologically positive individuals with virus neutralization activity (misidentified 1/20 unknowns compared to 2/20 for RBD and NP IgG). CONCLUSIONS: The coupling of virus neutralization analysis to a spike IgG3 antibody test is optimal to categorize patients for correlates of SARS-CoV-2 immune protection status.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19/diagnosis , Neutralization Tests/methods , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibodies, Viral/isolation & purification , COVID-19/blood , COVID-19/epidemiology , COVID-19/immunology , Enzyme-Linked Immunosorbent Assay , False Positive Reactions , Female , Humans , Immunity, Humoral , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin G/isolation & purification , Male , Middle Aged , Predictive Value of Tests , Prevalence , SARS-CoV-2/isolation & purification , Sensitivity and Specificity , Seroepidemiologic Studies , Spike Glycoprotein, Coronavirus/immunology , Young Adult
8.
Cell ; 183(5): 1367-1382.e17, 2020 11 25.
Article in English | MEDLINE | ID: covidwho-893667

ABSTRACT

A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a 5-fold lower dose. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible to escape mutations, and exhibit a lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Nanoparticles/chemistry , Protein Domains/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Vaccination , Adolescent , Adult , Aged , Animals , COVID-19/virology , Chlorocebus aethiops , Cohort Studies , Epitopes/immunology , Female , HEK293 Cells , Humans , Macaca nemestrina , Male , Mice, Inbred BALB C , Middle Aged , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , Vero Cells , Young Adult
9.
Res Sq ; 2020 Aug 13.
Article in English | MEDLINE | ID: covidwho-725304

ABSTRACT

The recently emerged SARS-CoV-2 virus is currently causing a global pandemic and cases continue to rise. The majority of infected individuals experience mildly symptomatic coronavirus disease 2019 (COVID-19), but it is unknown whether this can induce persistent immune memory that might contribute to herd immunity. Thus, we performed a longitudinal assessment of individuals recovered from mildly symptomatic COVID-19 to determine if they develop and sustain immunological memory against the virus. We found that recovered individuals developed SARS-CoV-2-specific IgG antibody and neutralizing plasma, as well as virus-specific memory B and T cells that not only persisted, but in some cases increased numerically over three months following symptom onset. Furthermore, the SARS-CoV-2-specific memory lymphocytes exhibited characteristics associated with potent antiviral immunity: memory T cells secreted IFN-γ and expanded upon antigen re-encounter, while memory B cells expressed receptors capable of neutralizing virus when expressed as antibodies. These findings demonstrate that mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks associated with antiviral protective immunity.

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